Development of a novel molecular target drug for cancer therapy.

• Project/Area Number: 15K14407
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Osaka University
• Principal Investigator: NOJIMA HIROSHI 大阪大学, 微生物病研究所, 教授 (30156195)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: サイクリンG1 / PP2A-B’γ / アポトーシス / 骨肉腫細胞 / 前立腺癌細胞 / 正常細胞 / ペプチド / 分子標的薬 / Cyclin G1 / PP2A B subunit / 分子標的薬剤 / DNA二重鎖切断 / がん遺伝子治療 / p53-S46 / DNA二重鎖切断 （DSB）

Outline of Final Research Achievements

Here, we found that ELAS1, a twentynine amino acid peptide corresponding to the association domain of Cyclin G1 with protein phosphatase 2A, interacts with the B' gamma subunit of PP2A and competitively inhibits the association with Cyclin G1. We showed that ELAS1 induced apoptotic cell death in U2OS, a human osteosarcoma cells through prevention of dephosphorylation at Mdm2 pT218 and p53 pS46, following DNA double-strand break insults such as gamma-irradiation and irinotecan treatment. We also show that ELAS1 caused apoptosis in prostate adenocarcinoma DU145 cells and tongue squamous-cell carcinoma SAS cells, but not in normal KD cells. The adenovirus that express ELAS1 also killed SAS cells. Notably, Cy5 tagged ELAS1t, which contained only ten amino acids, also efficiently induced apoptosis in both DU145 and SAS cells, suggesting the usefulness of ELAS1t itself as a peptide. Taken together, our results suggest that ELAS1 is therapeutically useful as a peptide drug.

Research Products

• [Journal Article] GAK is phosphorylated by c-Src and translocated from the centrosome to chromatin at the end of telophase. (2017)
  • Author(s): Fukushima K, Wang M, Naito Y, Uchihashi T, Kato Y, Mukai S, Yabuta N, Nojima H.
  • Journal Title: Cell Cycle Volume: 16 Issue: 5 Pages: 415-427
  • DOI: 10.1080/15384101.2016.1241916
  • Peer Reviewed
• [Journal Article] LATS2 Positively Regulates Polycomb Repressive Complex 2. (2016)
  • Author(s): Torigata K, Daisuke O, Mukai S, Hatanaka A, Ohka F, Motooka D, Nakamura S,Ohkawa Y, Yabuta N, Kondo Y, Nojima H.
  • Journal Title: PLoS One Volume: 11 Issue: 7 Pages: e0158562-e0158562
  • DOI: 10.1371/journal.pone.0158562
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] AJUBA LIM Proteins Limit Hippo Activity in Proliferating Cells by Sequestering the Hippo Core Kinase Complex in the Cytosol. (2016)
  • Author(s): Jagannathan R, Schimizzi GV, Zhang K, Loza AJ, Yabuta N, Nojima H, Longmore GD.
  • Journal Title: Molecular Cell Biology Volume: 36 Issue: 20 Pages: 2526-2542
  • DOI: 10.1128/mcb.00136-16
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Large tumor suppressors 1 and 2 regulate Aurora-B through phosphorylation of INCENP to ensure completion of cytokinesis. (2016)
  • Author(s): Yabuta N, Yoshida K, Mukai S, Kato Y, Torigata K, Nojima H.
  • Journal Title: Heliyon Volume: 2 Issue: 7 Pages: e00131-e00131
  • DOI: 10.1016/j.heliyon.2016.e00131
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comprehensive phenotypic analysis of knockout mice deficient in cyclin G1 and cyclin G2. (2016)
  • Author(s): Ohno S, Ikeda JI, Naito Y, Okuzaki D, Sasakura T, Fukushima K, Nishikawa Y, Ota K, Kato Y, Wang M, Torigata K, Kasama T, Uchihashi T, Miura D, Yabuta N, Morii E, Nojima H.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 39091-39091
  • DOI: 10.1038/srep39091
  • Peer Reviewed / Open Access
• [Journal Article] ELAS1-mediated inhibition of the cyclin G1-B'γ interaction promotes cancer cell apoptosis via stabilization and activation of p53. (2015)
  • Author(s): Ohno S, Naito Y, Mukai S, Yabuta N, Nojima H.
  • Journal Title: Oncogene Volume: 34 Pages: 5983-5996
  • Peer Reviewed
• [Journal Article] Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP. (2015)
  • Author(s): Chen Q, Zhang N, Xie R, Wang W, Cai J, Choi KS, David KK, Huang B, Yabuta N, Nojima H, Anders RA, Pan D.
  • Journal Title: Genes & Development Volume: 29 Issue: 12 Pages: 1285-1297
  • DOI: 10.1101/gad.264234.115
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Withaferin A induces cell death selectively in androgen-independent prostate cancer cells but not in normal fibroblast cells. (2015)
  • Author(s): Nishikawa Y, Okuzaki D, Fukushima, K, Mukai S, Ohno S, Ozaki Y, Yabuta N, Nojima H.
  • Journal Title: PLoS One Volume: 10 Issue: 7 Pages: e0134137-e0134137
  • DOI: 10.1371/journal.pone.0134137
  • Peer Reviewed / Open Access
• [Presentation] GAKがリン酸化した TAp63はLCE1C 遺伝子を特異的に転写誘導する。 (2016)
  • Author(s): 太田知絵、篠倉悠久、奥崎大介、福島孝士朗、向井智美、藪田紀一、野島 博
  • Organizer: 第３９回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] G1/SライセンシングにおけるGAKによるpRbのリン酸化の分子制御機構 (2016)
  • Author(s): 加藤依香、福島孝士朗、松浦克磨、藪田紀一, 野島博,
  • Organizer: 第３９回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] ELAS1 peptide caused apoptosis in both adenocarcinoma and squamous cell carcinoma (2016)
  • Author(s): Kaori Ota, Toshihiro Uchihashi, Yusuke Yabuno, Mikihiko Kogo, Norikazu Yabuta and Hiroshi Nojima
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-06
• [Presentation] サイクリンG1/G2欠損マウスの表現型解析 (2015)
  • Author(s): 太田香織、池田純一郎、大野将一、向井智美、鳥形康輔、内藤陽子、王冕、奥崎大介、藪田紀一、三浦大作、森井英一、野島博
  • Organizer: 第３８回日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-12-01
• [Presentation] Cyclin G-associate dkinase(GAK) phosphorylates TAp63 to upregulate expression of LCE1C gene (2015)
  • Author(s): 太田知絵, 向井 智美, 太田香織、奥崎大介、藪田 紀一,野島 博
  • Organizer: 第３８回日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-12-01
• [Presentation] Phosphorylations of ZEB1 by LATS1 and LATS2 regulate EMT-MET plasticity in breast cancer cells (2015)
  • Author(s): 向井 智美、鳥形康輔、藪田 紀一, 野島 博
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-10
• [Remarks] 大阪大学微生物病研究所・分子遺伝研究分野ホームページ
  • URL: http://www.biken.osaka-u.ac.jp/lab/molgenet/
• [Remarks]
  • URL: http://molgenet.biken.osaka-u.ac.jp/index.html